Dry powder pharmaceutical formulation

ABSTRACT

There is described a solid particulate pharmaceutical formulation suitable for application to the nose comprising finely divided additive particles and finely divided drug particles, wherein the mass median diameter of the drug particles is greater than that of the additive particles.

This application is a 371 of PCT/SE99/01990 filed Nov. 3, 1999.

This invention relates to a new pharmaceutical formulation and tomethods for its preparation and use.

Conditions of the nose, and in particular allergic conditions whicheffect the nose, occur in an ever increasing proportion of thepopulation. Such conditions are often treated by the administration ofappropriate topically active medicines to the nose either by means ofpressurised aerosol, liquid (usually aqueous) or dry powder formulationsof the required drug. The dry powder formulations are often the same as,or slight modifications of, inhalation formulations of the same drug foruse in the treatment of the lung. Such inhalation formulations containthe drug in the form of very fine particles intended to reach deep intothe lung.

The very fine particles of the drug used in inhalation formulations aredifficult to handle because of the Van der Waal's forces which make themhighly cohesive. In order to overcome this the fine particles of drug(optionally in admixture with fine particles of a carrier or diluent)can be agglomerated into larger pellets which are sufficiently large andsufficiently strong to be easily handled, but which are sufficientlyweak to break up into the individual fine particles on inhalation.Alternatively the fine particles of drug can be mixed with a coarsecarrier to provide a free flowing mixture which again yields the fineparticles on inhalation.

When formulations which are designed principally for inhalation are usedto treat the nose they are likely to be less than optimal for suchtreatment, partly because some of the fine particles of drug passthrough the nose and reach the pharynx, trachea and lung. This isundesireable in that the portion of drug not remaining in the nose islikely to be ineffective for the treatment of a nasal condition and alsomay cause unwanted side effects in the other organs.

We have now found that these disadvantages can be overcome by usinglarger particles of the drug. However the particles of the drug shouldstill be small enough to be dispersed widely over the nasal mucosa.

These larger, but still relatively small, particles are much lesscohesive than the very small particles used in inhalation formulations,but they are still generally insufficiently free flowing to enable themto be handled easily in pharmaceutical production, eg on automatedmachines, or to fill into the dosing chamber of a multidose nasalinhaler, or to spread evenly over the nasal mucosa.

We have now found a means of formulating these larger, but stillrelatively small particles so that these problems can be overcome.

Thus according to the invention we provide a solid particulatepharmaceutical formulation suitable for application to the nosecomprising finely divided additive particles and finely divided drugparticles, wherein the mass median diameter of the drug particles isgreater than that of the additive particles.

We prefer at least 85% of the drug particles to have a size over 5 μm,and at least 90% a size of less than 20 μm.

We prefer at least 85%, and more preferably at least 70% of the drugparticles to have a size below 15 μm.

We prefer at least 90% of the additive particles to be of a size of lessthan 10 μm.

We further prefer at least 80% of the additive particles to be of a sizeof less than 7 μm, and more preferably not more than 10% of the additiveparticles to be of a size of less than 1 μm.

In this specification percentages are by weight, and sizes are measuredby conventional means, e.g. by a Coulter counter or by a laser particlesize analyser (e.g. Malvern).

The proportion of the additive and the drug will vary according to theparticular drug and additive. Thus with a potent drug the proportion ofthe additive will generally be higher than with a less potent drug. Ingeneral we prefer the proportion to be from 99.6 to 0.4, and morepreferably from 20 to 0.5, and especially about 1, parts by weight ofadditive to one part by weight of drug.

The mixture according to the invention may be agglomerated usingconventional techniques known per se to produce pellets having a size offrom 10 to 2,000, and preferably of from 10 to 1,000 μm. The pellets ofthe invention contain both drug and additive. The individual componentsof the mixture may be made of the desired particle size by milling,micronising, sieving, direct synthesis, or by other conventionaltechniques for the preparation of particles within a desired size range.

The drugs which may be used in the formulations of the invention arethose which are conventionally applied to the nose. The drugs may beused for the treatment of conditions of the nose, or may be applied tothe nose to have their effect in some other part of the body. Classes ofdrugs used to treat conditions of the nose include antiallergic drugs,for example antihistamines, e.g. loratidine or terfenadine;anti-inflammatories for example steroids, e.g budesonide (including the21-(3-sulphopropionate) thereof), ciclesonide, fluticasone, mometasone,tipredane, flumethasone acetonide, triamcinolone acetonide,beclomethasone, RPR-106541, anticholinergic agents, e.g. ipratropiumbromide, thiotropium bromide and oxytropium bromide; azelastine,levocabastine, sodium cromoglycate, nedocromil sodium; andvasoconstrictors. Other clases of drugs suitable for use in theinvention include proteins, peptides such as insulin, hormones etc.Mixtures of one or more such drugs may also be used. Salts, solvates,hydrates and esters of the above drugs can also be used when such areformed, for example esters of mometasone such as the furoate ester andhydrates thereof. Preferred drugs include budesonide and mometasoneparticularly in the form of the furoate ester of mometasone and hydratesthereof.

The additive may be a carrier, diluent or other excipient (e.g. anabsorption enhancer such as sodium taurocholate, or an antioxidant)which imparts desired properties to the formulation.

The carrier may be any suitable carrier which is acceptable to the nasalmucosa. Such carriers are well known and include carbohydrates andespecially sugars, e.g. sucrose. The preferred carrier is lactose, e.gin the form of its monohydrate.

The particles and formulations according to the invention may beadministered to the nose using a variety of devices known for theadministration of drugs to the nose. We particularly prefer to use thedry powder device known as Turbuhaler®.

The invention is illustrated, but in no way limited, by the followingExample.

EXAMPLE

Budesonide and lactose monohydrate were separately micronised usingconventional techniques known per se. The budesonide particles (whichhave optionally been conditioned according to the process of WO95/05805)had a mass median diameter of 7.0 μm and the lactose particles had amass median diameter of 2.5 μm, and were conditioned as described inWO95/05805. 90 mg of the micronised budesonide was made up to a totalweight of 1 g by admixture with the micronised and conditioned lactoseand spheronised and sieved using conventional techniques to produce softpellets of a size of less than 0.8 m.

What is claimed is:
 1. A solid particulate pharmaceutical formulationfor application to the nose comprising finely divided additive particlesand finely divided drug particles, wherein the mass median diameter ofthe drug particles is greater than that of the additive particles.
 2. Aformulation according to claim 1, wherein 85% of the drug particles havea size over 5 μm and at least 90% have a size of less than 20 μm.
 3. Aformulation according to claim 1, wherein at least 90% of the additiveparticles are of a size of less than 10 μm.
 4. A formulation accordingto claim 3, wherein at least 80% of the additive particles are of a sizeof less than 7 μm, and not more than 10% of the additive particles areof a size of less than 1 μm.
 5. A formulation according to claim 1,wherein the proportion by weight of the additive and the drug is in therange of from 99.6 to 0.4:1.
 6. A formulation according to claim 5,wherein the proportion is from 20 to 0.5:1.
 7. A formulation accordingto claim 1, wherein the formulation is in the form of agglomerates of asize from 10 to 2,000 μm.
 8. A formulation according to claim 1, whereinthe drug is an anti-inflammatory or anti-allergic drug.
 9. A formulationaccording to claim 1, wherein the drug is budesonide.
 10. A formulationaccording to claim 1, wherein the drug is mometasone or the furoateester of mometasone and hydrates thereof.
 11. A formulation according toclaim 1, wherein the additive is a carrier.
 12. A formulation accordingto claim 11, wherein the carrier is lactose.
 13. A device for theapplication of a drug to the nose containing a formulation according toclaim 1.